Various forms of inflammation are characterized by activation of macrophages. Macrophages are thought to induce and maintain inflammatory processes mainly by producing various products that, by acting on other cells, bring about the deleterious consequences of inflammation. For example, macrophages produce cytokines. These proteins are central mediators in inflammatory processes, such as the local inflammatory processes characteristic of arthritis or colitis. Cytokines produced by macrophages are also thought to be involved in systemic inflammatory processes, such as endotoxic shock. Macrophage products are more generally involved in pathophysiological mechanisms, such as plasma extravasation, inflammatory cell diapedesis, release of toxic free radicals, endothelial injury, and release of tissue degrading enzymes, which can result in tissue injury and, ultimately, organ failure.
Tumor necrosis factor (TNF) is a cytokine associated with macrophage activation. TNF is also thought to be involved in inducing most of the pathophysiological events characteristic of inflammation. For example, TNF is a key cytokine in associated with the toxic effect of endotoxin (LPS) and in the pathogenesis of septic shock, as evidenced by high serum plasma levels of TNF after LPS administration to animals or to human volunteers, or in septic subjects. Administration of anti-TNF antibodies protects against the lethal effects of LPS and of live bacteria in a variety of animal models. Moreover, TNF can be a central target in the treatment of rheumatoid arthritis.
Interleukin-12 (IL-12) is another macrophage product that has been shown to be involved in the induction of pathology in several inflammatory diseases. These diseases include autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, insulin dependent diabetes mellitus, and rheumatoid arthritis, and inflammatory states such as septic shock and the generalized Schwarzman reaction. For example, administration of anti-IL-12 antibodies substantially reduces the incidence and severity of adoptively transferred experimental allergic encephalomyclitis, suggesting that endogenous IL-12 is involved in its pathogenesis. Furthermore, the course of disease in adjuvant-induced arthritis is suppressed in IL-12 deficient mice, or in mice treated with anti-mIL-12 antibodies.
The chemokine macrophage inflammatory protein (MIP)-1a and the CXC chemokine MIP-2 are additional proinflammatory proteins expressed by macrophages.
IDDM (insulin-dependent diabetes mellitus), Type 1 diabetes, is a consequence of the destruction of pancreatic β-cells. Rabinovitch, A. and Wilma L. Suarez-Pinzon, Cytokines and Their Roles in Pancreatic Islet β-Cell Destruction and Insulin-Dependent Diabetes Mellitus, Biochemical Pharmacology, Vol. 55, 1998, pp. 1139-1149. The Type 1 cytokines, produced by Th1 cells, cause destruction of pancreatic β-cells. Type 2 cytokines, produced by Th2 cells, suppress the activity of the Type 1 cytokines. Almawi, et al., T Helper Type 1 and 2 Cytokines Mediate the Onset and Progression of Type I (Insulin-Dependent) Diabetes, JCE & M, Vol. 84, No. 5, 1999, pp. 1497-1502 discloses that both Th1 and Th2 cells affect the onset and the progression of type I diabetes.
U.S. Pat. No. 6,342,484 to Kulkami et al. discloses that inosine promotes healing in a diabetic patient.
Kuninaka et al, Flavor Activity of Sulfur-containing Compounds Related to Flavor Nucleotides, Agric. Biol. Chem, 44 (6), 1980, pp. 1437-1439 discloses that inosine-5′-monophosphate, inosine-5′-monosulfate, inosine-2′,(3′), 5′-diphosphate and inosine-2′,(3′), 5′-disulfate affect taste sensation.
U.S. Pat. No. 5,614,504 to Hadden et al. discloses a method of preparing methyl 5′-inosine monophosphate (MIMP) and its use for reversing inflammation and physical trauma.
Jurkowitz et al., Adenosine, Inosine, and Guanosine Protect Gilian Cells During Glucose Deprivation and Mitochondrial Inhibition: Correlation Between Protection and STP Preservation, J. Neurochem., Vol. 71, No. 2, 1998, pp. 535-548 discloses that inosine can delay cell death by retarding the decline of ATP.
G. Hasko et al., Abstracts, Blood, Vol. 94, No. 10, 1999, p. 427a, Abstract No. 1893 discloses that inosine can suppress proinflammatory cytokine production and reduce mortality in a mouse endotoxemic model.
Haskó et al., Inosine Inhibits Inflammatory Cytokine Production by a Posttranscriptional Mechanism and Protects Against Endotoxin-Induced Shock, J. Immunol., 2000, pp. 1013-1019 discloses using inosine to inhibit the production of proinflammatory cytokines.
K. Wada et al., Inosine Monophoshpate and Aspirin-Triggered 15-Epilipoxin A4 Act in Concert to Regulate Neutrophil Trafficking: Additive Actions of Two New Endogeneous Anti-Inflammatory Mediators, J. Hematother. Stem Cell Res. 2001, vol 10, pp. 75-79 discloses that inosine 5′-monophosphate and aspirin have an additive effect in resolving inflammatory response.
U.S. Pat. No. 6,060,459 to von Borstel et al. discloses using particular alky- or acyl-substituted inosine derivatives for treating inflammation diseases.
International Patent Publication No. WO 96/33203 discloses that inosine 5′-methylphosphate can reverse inflammation.
F. -H. Qui et al., IMP and AMP Deaminase in Reperfusion Injury Down-Regulates Neutrophil Recruitment, Proc. Natl. Acad. Sci. U.S.A., 2000, vol. 97, pp. 4267-4272 discloses that inosine can regulate neutrophils and play a role in inflammation and reperfusion.
M. P. Veerabagu et al., Intravenous Nucleosides and a Nucleotide Promote Healing of Small Bowel Ulcers in Experimental Enterocolitis, Digestive Diseases and Science 41, 1996, pp. 1452-1457 discloses the parenteral administration of a composition comprising inosine, cytidine, sodium 5′-guanylate, uridine and thymidine for the treatment bowel ulcers.
R. Norton et al., Use of Nucleotides in Weanling Rats with Diarrhea Induced by a Lactose Overload: Effect on the Evolution of Diarrhea and Weight and on the Histopathology of Intestine, Liver, and Spleen, Braz. J. Med. Biol. Res. 2001, vol. 34, pp. 195-202 discloses that a composition comprising inosine monophosphate, adenosine monophosphate, cytidine monophosphate, and uridine monophosphate improved the intestinal inflammatory response.
There remains, however, a clear need for compounds, compositions and methods that are useful for treating or preventing an inflammation disease, particularly inflammatory bowel disease, or a reperfusion disease.
Citation or identification of any reference in Section 2 of this application is not to be construed as our admission that such reference is prior art to the present application.